INvestigating COPD Outcomes, Genomics and Neutrophilic Inflammation With Tiotropium and Olodaterol

BACKGROUND Inhaled corticosteroids (ICS) are commonly prescribed for patients with chronic obstructive pulmonary disease (COPD), but their role in the management of COPD is currently being re-evaluated in light of new evidence and the emergence of alternative treatments. Recent concerns have been expressed about the safety of ICS in COPD following several randomized controlled trials of fluticasone propionate and fluticasone furoate demonstrating an increase in rates of pneumonia as an adverse event. Several systematic reviews and observational studies confirm an association between ICS use and risk of pneumonia. A series of post-hoc analyses of large randomized controlled trials of ICS/ long acting beta-agonists (LABA) or ICS alone have suggested that benefits of ICS in terms of exacerbation reduction and preventing lung function decline are limited to a subgroup of patients with eosinophilic airway inflammation. Eosinophils are highly sensitive to ICS, and so there is a compelling rationale for this association, and therefore an emerging consensus that ICS should be reserved for those patients with eosinophilic disease. This can be identified on the basis of blood eosinophil count although the precise cut-off is yet to be determined. This is strongly supported by a post-hoc analysis of the WISDOM randomized controlled trial of ICS withdrawal in which ICS withdrawal was only associated with an increase in exacerbations above blood eosinophil counts of 300 cells per ul. Furthermore in the FLAME study which excluded patients with very high eosinophils counts, LABA/long acting muscarinic antagonists (LAMA) was superior to ICS/LABA in terms of reducing exacerbations. If there is an emerging consensus regarding the treatment of "eosinophilic COPD", then the unmet need in the management of COPD is for the majority of patients that have neutrophilic airway inflammation. Neutrophilic inflammation does not respond to inhaled corticosteroids and indeed there is in-vitro evidence that inhaled corticosteroids may exacerbate neutrophilic inflammation by delaying neutrophil apoptosis. Neutrophilic inflammation is associated with disordering of the lung microbiome with overgrowth of Proteobacteria, a process that may be exacerbated by ICS. Release of proteolytic enzymes such as elastase and matrix metalloproteinase from neutrophils are associated with disease progression and lung function decline in COPD. RATIONALE FOR STUDY It is hypothesised that the combination of tiotropium and olodaterol may be an ideal treatment option for patients with neutrophilic COPD because * Tiotropium and olodaterol have both been shown to have potentially beneficial effects in suppressing neutrophilic inflammation without impairing bacterial killing * These effects may reverse the detrimental impact of inhaled corticosteroids on airway neutrophil function and the microbiome. In particular olodaterol was evaluated in cigarette smoke- and Lipolpolysaccharide - induced- models of neutrophil lung inflammation in mice and guinea pigs. The results showed Olodaterol to suppress neutrophil recruitment to the lung (by up to 90%) while preserving chemotactic function (which is required for effective phagocytosis of pathogens). Tiotropium has also been extensively investigated and is known to suppress neutrophil recruitment and neutrophil dependent remodelling in a number of in-vivo models and may work synergistically with olodaterol in reducing neutrophil retention in the lung. This extensive preclinical work justifies a study of olodaterol/tiotropium in human subjects evaluating its impact on neutrophilic inflammation. This could establish the combination of olodaterol/tiotropium as the first line therapy for patients with neutrophilic COPD. This trial will compare treatment of patients with COPD previously treated with ICS randomized to either tiotropium/olodaterol combination or fluticasone furoate/vilanterol combination. The objective of the trial is to evaluate in-vivo effects of these drugs on the lung microbiota and airway neutrophil function. In particular, we expect that 6 months treatment with olodaterol/tiotropium will result in a reduced airway bacterial load (through restored neutrophil function allowing neutrophils to kill airway bacteria), an increase in microbiota diversity, an enhanced ex-vivo killing of Haemophilus influenzae and reduced markers of neutrophilic airway inflammation. HYPOTHESIS Tiotropium and olodaterol combination treatment will result in a reduced airway bacterial load at 6 months compared to fluticasone furoate and vilanterol. The reduced bacterial load will be associated with improvements in the airway microbiota and reduced markers of neutrophilic inflammation and restored neutrophil function.